Circulating urotensin II levels in moderate to severe congestive heart failure: Its relations with myocardial function and well established neurohormonal markers
Introduction
Urotensin II (UII) is a cyclic undecapeptide, first isolated from teleost fish and later identified in mammals. UII possesses multiple effects on the cardiovascular system, mediated through activation of G-protein coupled receptors. In rat thoracic aorta and non-human primates isolated arteries, UII is the most potent vasoconstrictor identified so far [1]. The potent vasoconstrictor effects of UII have also been observed in other species, but were dependent upon the anatomical origin of the vessels studied [3], [13]. UII may act as a potent vasodilator in human small pulmonary arteries and abdominal arteries [17] and rat small arteries [2]. Endothelium derived NO is involved in this UII-induced vasodilation [6], [21]. UII exhibits also controversial effects on cardiac contractility. UII has been shown to have profound negative inotropic effects in non-human primates [1], but a cardiostimulant effects on human myocardium in vitro has been reported [15]. In addition, UII causes cardiomyocyte hypertrophy, smooth muscle cell proliferation and stimulates extra-cellular matrix production [13], [18]. Myocardial UII expression is strongly upregulated in end-stage congestive heart failure (CHF), together with an increase of its binding sites [4]. Circulating UII measured by specific immunoassay after plasma extraction is elevated in severe CHF patients [12], but according to one study was not related to NYHA classes [9]. Natriuretic peptides, endothelin-1 and their precursors are established markers of ventricular function. The relation of UII with BNP and Nt-proBNP in plasma of CHF patients is controversial and no data directly compare UII to Nt-proANP and Big-ET1, another marker for diagnosis and prognosis in CHF [11], [20].
Therefore, the aim of the present study was to measure plasma UII by RIA in control subjects and patients with moderate to severe CHF and to evaluate its relationship with the NYHA functional class as well as the ejection fractions. We also analyzed in CHF patients circulating levels of BNP, Nt-proANP and Big-ET1 to determine the relative place of plasma UII as a marker of CHF, in relation to these well established neurohormonal markers.
Section snippets
Study population
Fifty-seven CHF patients and 48 matched controls for gender and age were included in the study. All patients gave informed consent. Forty-five patients had ischemic cardiomyopathy; 10 had dilated cardiomyopathy and two presented a valvular cardiopathy. Left ventricular ejection fraction (LVEF) was determined by contrast or isotopic ventriculography. Functional status was determined according to the New York Heart Association (NYHA) by an experienced cardiologist (M.F.R.) blinded to all other
Patients characteristics
Age and gender ratios were equivalent in controls, moderate and severe CHF patients. All CHF patients had confirmed LVEF <40%. Mean LVEF was significantly higher in moderate than in severe CHF patients (24% versus 18%, p < 0.05) (Table 1).
Plasma levels of UII in congestive heart failure
UII plasma levels were 43% higher in the CHF group than in controls [1.32 (0.67–2.59) versus 0.84 (0.31–1.61), respectively, p < 0.0001, geometric mean (pg/ml) with 95% PI; n = 57 versus 48]. Moreover, as show in Fig. 1A, plasma UII was significantly related to the
Discussion
The present study indicates that circulating UII is elevated in CHF and significantly correlated to functional class and systolic function. Using immunoassays after plasma extraction, three other groups have reported increased UII in CHF [9], [12], [14]. Richards et al. [12], showed a two-fold increase in venous plasma UII in severe CHF compared to controls, but no stratification according to NYHA classification was described. Russell et al. [14] observed increased UII plasma levels from aortic
References (23)
- et al.
Congestive heart failure and expression of myocardial urotensin II
Lancet
(2002) - et al.
Plasma levels and cardiovascular gene expression of urotensin-II in human heart failure
Regul Pept
(2002) - et al.
Human urotensin II increases coronary perfusion pressure in the isolated rat heart: potentiation by nitric oxide synthase and cyclooxygenase inhibition
Life Sci
(2001) - et al.
Elevated plasma human urotensin-II-like immunoreactivity in ischemic cardiomyopathy
Int J Cardiol
(2004) - et al.
Prognostic impact of big endothelin-1 plasma concentrations compared with invasive hemodynamic evaluation in severe heart failure
J Am Coll Cardiol
(1996) Emerging roles of urotensin-II in cardiovascular disease
Pharmacol Ther
(2004)- et al.
MedCalc: a new computer program for medical statistics
Comput Methods Programs Biomed
(1995) - et al.
Urotensin II and cardiovascular diseases
Peptides
(2004) - et al.
Superiority of big endothelin-1 and endothelin-1 over natriuretic peptides in predicting survival in severe congestive heart failure: a 7-year follow-up study
J Card Fail
(2004) - et al.
Urotensin II induces hypertrophic responses in cultured cardiomyocytes from neonatal rats
FEBS Lett
(2001)
Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14
Nature
Cited by (53)
Novel insights into the role of urotensin II in cardiovascular disease
2019, Drug Discovery TodaySilymarin ameliorates expression of urotensin II (U-II) and its receptor (UTR) and attenuates toxic oxidative stress in the heart of rats with type 2 diabetes
2018, Biomedicine and PharmacotherapyCitation Excerpt :In human, the expression of U-II and UTR is upregulated in cardiovascular diseases, including heart failure, hypertension, and coronary artery disease [7] as well as type 2 diabetes [8,9]. There is a positive correlation between the extent of congenital heart failure (CHF) and plasma U-II concentrations [10,11] with 2.1-fold enhancement compared with controls [12]. Overexpression of the U-II in atherosclerotic lesions where infiltration of macrophage occurs [13], may accelerate the atherosclerosis through acting synergistically with mildly oxidized LDL (ox-LDL) level and activate proliferation of vascular smooth muscle cell (VSMC) [14].
Circulating levels of the vasoactive peptide urotensin II in patients with acute coronary syndrome and stable coronary artery disease
2014, PeptidesCitation Excerpt :This suggests that in the setting of cardiovascular events, UII is induced by inflammatory cytokines or vice versa rather than produced by the damaged myocardium. The present study also demonstrated a significant negative correlation between UII levels and EF, supporting previous findings by our and other research groups [20]. Higher UII levels in an acute setting with low cardiac contractility could be potentially beneficial given UII's has inotropic and vasodilatory effects [41,46,47].
Urotensin II prevents cardiomyocyte apoptosis induced by doxorubicin via Akt and ERK
2012, European Journal of PharmacologyPresence of urotensin-II receptors at the cell nucleus: Specific tissue distribution and hypoxia-induced modulation
2012, International Journal of Biochemistry and Cell Biology